Use of tazarotene for preparing a nail varnish for treating and/or preventing psoriasis and nail varnish containing same

ABSTRACT

The invention concerns the use of tazarotene for preparing a nail varnish for treating and/or preventing psoriasis and nail varnish containing tazarotene and method for making same. More particularly, the invention concerns a nail varnish containing additionally to tazarotene a film-forming agent soluble or insoluble in polar solvents and physiologically acceptable solvents. Optionally it contains a penetration agent.

The present invention relates to the use of tazarotene for preparing anail varnish for treating and/or preventing psoriasis, to a nail varnishcontaining tazarotene, and to a method of production.

Psoriasis is a skin disease which affects more than two percent ofwestern populations.

It results in chronic erythematosquamous dermatosis. The lesion combineskeratinocyte abnormalities (greatly increased mitotic activity andabnormal differentiation) with dermal and epidermal inflammatoryphenomena.

The disease is controlled by genetic factors, which are revealed byvarious environmental factors.

Nail conditions due to psoriasis are persistent disease forms which ithas not been possible, up until now, to treat satisfactorily. Theyaffect, depending on the country, between 10 and 78% of populationsdeveloping psoriasis.

Today, the most widespread treatment for nail psoriasis consists ofsubcutaneous injections of corticoids.

These corticoids are anti-inflammatory active principles widely used fordermatological treatments.

These very painful injections can be accompanied by topical treatment.

Another treatment consists in applying locally to the nails specificsubstances with antipsoriatic action, in the form of a cream. In thisfield, the most diverse methods of treatment have been tried. Thus, in acombined treatment, the nails have first been treated with solutions ofsubstances with antipsoriatic action and dressings have been appliedwith cream overnight. This method of treatment is also very unpleasantand psychologically trying for the patients. Firstly, it is necessary totreat the nails several times a day. Secondly, the nails must be wrappedin dressings, especially overnight. Consequently, the treatment, whichusually lasts several months, is not commonly pursued by the patients,who, on the contrary, become discouraged and neglect the treatment. Thisresults in the treatment failing. In this method, the success of thetreatment is also compromised by the fact that the solutions and thecreams are usually water-miscible or hydrophilic and can be removed fromthe surface of the nail or entrained away from the nail by dissolutionwhile washing, taking a bath or having a shower, and must therefore thenbe applied again.

Tazarotene is a retinoid derivative known for its antipsoriaticactivity.

It is a retinoid derivative, also known as ethyl6-[(3,4-dihydro-4,4-dimethyl-2H-1-benthiopyran-6-yl)ethynyl]-3-pyridinecarboxylate,of formula

It may in particular be in the form of a cream or a gel.

However, while the effectiveness of tazarotene on plaques of psoriasishave been demonstrated, treating psoriasis which develops under thenails is delicate.

It is difficult to reach effective concentrations of active principle soas to eliminate the psoriasis under these conditions.

It has now been found that it is possible to treat nail psoriasissuccessfully and/or to prevent it by applying the nail varnish accordingto the invention to the nails, and in particular to the nails affectedby psoriasis.

A subject of the present invention is therefore the use of tazarotenefor preparing a nail varnish for treating and/or preventing psoriasis.

A second subject of the invention is a nail varnish with antipsoriaticaction containing tazarotene.

The nail varnish according to the invention advantageously contains afilm-forming agent which is soluble or insoluble in polar solvents.

The subject of the present invention is also a nail varnish containing,besides tazarotene and a film-forming agent which is soluble orinsoluble in polar solvents,

-   a) one or more physiologically acceptable solvents suitable for the    type of film-forming agent used,-   b) optionally, one or more penetration agents and, optionally,-   c) additives conventionally used in cosmetics.

According to the invention, the nail varnish should contain sufficientactive principle so that, when it is deposited on the nail, this allowsan appropriate release ensuring diffusion up to the nail bed, and thusmaking it possible to attain the therapeutic threshold.

Another subject of the present invention is a method for producing thenail varnish according to the invention, which comprises a stepconsisting in mixing a film-forming agent and tazarotene.Advantageously, when the nail varnish which is the subject of thepresent invention contains constituents a), b) and/or c), mentionedabove, other than the active principle and the film-forming agent, theactive principle and the other constituents are dissolved in thesolvent(s) before the film-forming agent.

The nail varnishes according to the invention may contain film-formingagents which are soluble in aqueous-alcoholic solvents or nonpolarsolvents which, after drying on the nail, form water-resistant films.Suitable film-forming agents which are soluble in nonpolar solvents (orinsoluble in polar solvents) include substances based on cellulosenitrate or on synthetic polymers well known to the formulator for theirinnocuity. Mention may be made, for example, of poly(vinyl acrylate) andpartially saponified poly(vinyl acrylate), copolymers of first vinylacetate and secondly acrylic acid or crotonic acid or a monoalkylmaleate, ternary copolymers of firstly vinyl acetate and secondlycrotonic acid and vinyl neodecanoate or crotonic acid and vinylpropionate, copolymers of vinyl methyl ether and of a monoalkyl maleate,in particular in the form of monobutyl maleate, copolymers of fatty acidvinyl esters and of acrylic acid or of methacrylic acid, copolymers ofN-vinylpyrrolidone, methacrylic acid and alkyl methacrylate, copolymersof acrylic acid and of methacrylic acid, or of alkyl acrylate or ofalkyl methacrylate, poly(vinyl acetals) and poly(vinyl butyrals),poly(N-vinylpyrrolidones) substituted with alkyl groups, alkyl esters ofcopolymers of olefin and of maleic anhydride and products from reactionof rosin and of acrylic acid. In the ester, the alkyl residues areusually short chains and generally contain no more than four carbonatoms.

Suitable film-forming agents which are soluble in polar solvents includepolyacrylamides; acrylic/methacrylic, polymethacrylate/butyl acrylateand acrylic/acrylate copolymers; polyvinyl alcohol; poly(vinyl methylether)/maleic anhydride copolymer; polyvinyl-pyrrolidone;polyvinylpyrrolidone/vinyl acetate copolymer andvinylpyrrolidone/dimethylaminoethyl methacrylate copolymer.

A mixture of film-forming agents of the same class (soluble in polarsolvents or else soluble in nonpolar solvents) can be used asfilm-forming agent in the context of the invention.

Among the film-forming agents which are soluble in polar solvents,preference is given to acrylic/acrylate and acrylic/methacrylatecopolymers or the acrylic/acrylate/methacrylate tercopolymer.

Among the film-forming agents which are soluble in nonpolar solvents,preference is given to the vinyl methyl ether/monobutyl maleatecopolymer.

Among the physiologically acceptable solvents, and as nonpolar solvents,mention may be made of substances such as hydrocarbons, halogenatedhydrocarbons, alcohols, ethers, ketones and esters, commonly used incosmetics, in particular esters of acetic acid and of monoalcohols, suchas ethyl acetate and butyl acetate, optionally as a mixture witharomatic hydrocarbons such as toluene and/or alcohols such as ethanol orisopropyl alcohol. When a water-soluble film-forming agent is used asfilm-forming agent, use may be made, as solvent, in the context of thepresent invention, of alcohols such as ethanol, isopropyl alcohol or anyother alcohol having a boiling point sufficiently low to have a veryshort drying time. These alcohols may be present in the varnish in theform of mixtures, and an amount of water ranging from 0 to 20% by weightrelative to the total amount of solvent can then be added. These aresolvents referred to as aqueous-alcoholic solvents.

In the context of the present invention, and whether the film-formingagent is water-soluble or -insoluble, use is preferably made of acombination of solvents or solvent systems. These solvents arepredominantly important with respect to the drying time, the ease ofapplication with a brush and other important properties of the varnishor of the film of varnish. The solvent system may be between 70 and 94%by weight relative to the total weight of the varnish.

This solvent system is preferably a mixture of solvents with a lowboiling point (=boiling point up to 100° C.) and of solvents with amedium boiling point (=boiling point up to 150° C.), optionally with asmall proportion of solvents with a high boiling point (=boiling pointup to 200° C.).

As penetration agents, mention may in particular be made of urea, oleicacid and ethoxydiglycol. Any other penetration agent commonly used inthis type of formulation may also be used in the context of the presentinvention.

The nail varnishes according to the invention may also contain additivescommonly used in cosmetics, such as plasticizers based on phthalate,urea or camphor, colorants or colored pigments, a pearlescent agent,sedimentation retarders, sulfonamide resins, silicates, fragrances,wetting agents, such as sodium dioctyl-sulfosuccinate, lanolinderivatives, light-screening agents, such as2-hydroxy-4-methoxybenbzophenone, substances with antibacterial actionand substances with keratolytic and/or keratoplastic action, such asammonium sulfite, esters and salts of thioglycolic acid, urea,allantoin, enzymes and salicylic acid.

Colored or pigmented nail varnishes offer, for example, the advantagethat the composition according to the invention can be adapted to thepatient's esthetic preferences.

The nail varnish is prepared in the usual manner, by mixing of theindividual components and, if necessary, subsequent treatment adapted toeach composition.

In the nail varnish according to the invention, the tazarotene contentis generally an amount ranging from 0.1 to 4%, preferably from 0.1 to 2%by weight relative to the total weight of the composition.

The nail varnish according to the invention generally contains from 0.1to 30%, preferably from 5 to 20% by weight of film-forming agent, from69 to 99% by weight, preferably from 79 to 94%, and more precisely from81 to 86% by weight of solvent, and from 0.5 to 15% by weight,preferably from 1 to 10% and more precisely from 3 to 7% of penetrationagent relative to the total weight of the varnish.

The proportions mentioned above make it possible in particular to obtaina varnish suitable for the production chain while at the same timeexhibiting properties of ease of spreading and rapid drying.

It is known that the superficial cornified layers have, inter alia, thebiological function of preventing the penetration of foreign substances.The compositions according to the invention enable a considerableproportion of the active principle to pass through the 168 superficialcornified layers and thus to exert a long-lasting, deep action.

The present invention relates, moreover, as a particular embodiment, toa varnish as described above, also containing a corticoid or a mixtureof various corticoids.

The corticoids which can be combined with the tazarotene can be chosenfrom the corticoids having:

-   -   very high activity, among which are clobetasol propionate and        betamethasone dipropionate;    -   high activity, among which: betamethasone valerate or        dipropionate, fluocinolone acetonide and hydrocortisone        aceponate or butyrate;    -   quite high activity, among which: flucinolone acetonide, and        desonide;    -   moderate activity, among which: hydrocortisone acetate.

As nail varnish containing a corticoid, a nail varnish containingclobetasol or one of its pharmaceutically acceptable salts, such asclobetasol propionate, is preferred.

This corticoid classification is the European classification and is notlimiting for the invention. The amount of corticoid can range from 0.01%to 5% by weight relative to the total weight of varnish, as a functionof the seriousness of the psoriasis to be treated.

The present invention is illustrated in greater detail using thefollowing example.

EXAMPLE:

Study of the Activity of 6 Formulations of Varnish According to theInvention

In the tests on penetration capacity, several formulae were tested,prepared either with film-forming agents tending toward beinghydrophilic, dissolved in aqueous-alcoholic media, or with film-formingagents tending toward being hydrophobic, dissolved in relativelynonpolar solvents.

In the two cases, we concentrated on the non-solubilization in water,after drying, of the film formed, which would, when taking a wash, leadto the disappearance of the active principle and therefore to loss ofthe activity of the product.

A first series of tests was carried out on skin explants in order toverify, on this conventional model, whether we were able to discriminateseveral different formulae.

Using diffusion cells of the modified Franz cell type, the variousformulae were applied in finite doses, i.e. 9.2 mg/cm², to humanabdominal skin cut at 400 microns on a dermatome. Passage through wasstudied over 24 hours. The tazarotene active principle diffused throughthe skin and was collected in the recipient liquid at 3 h, 6 h, 12 h and24 h.

After 24 h, the active principle was assayed in the tissue, at the endof the diffusion phase (dermis and epidermis) and at the surface of thetissue, after having surface cleaned the varnish.

Two types of formulae were tested: Apolar formulae Polar formulae (in %)(in %) Gel 1 2 3 4 5 6 control TAZAROTENE 0.5 0.5 0.1 1 0.5 0.1 0.1B.H.T. 0.05 0.05 0.05 0.05 0.05 0.05 — UREA — 5 — — — — — COPOLYMER: 1414 14 — — — — ACRYLIC ACID/ METHYL METHACRYLATE/ ETHYL ACRYLATE PURIFIEDWATER 9.99 9.41 10.04 — — — — ETHANOL 75.46 71.04 75.81 — — — —COPOLYMER: — — — 15 15 15 — VINYL METHYL ETHER MONOBUTYL ESTER OF MALEICACID ISOPRANOL — — — 50.15 50.45 50.69 — ETHYL ACETATE — — — 33.80 34.0034.16 —B.H.T.: Butylated Hydroxytoluene

With polar film-forming agent in solvent (formulae 1, 2 and 3)

With nonpolar film-forming agent and solvent (formulae 5 3, 4 and 5)

We used a commercial control, known as Zorac®, a dermal gel containing adose of 0.1% of tazarotene.

Study of the transcutaneous passage of tazarotene over 24 hours. Passagein Characteristic micrograms Formula 1 Hydrophilic varnish 0.175 0.5%tazarotene 5% urea Formula 2 Lipophilic varnish 0.12 1% tazaroteneFormula 3 Lipophilic varnish 0.065 0.5% tazarotene Formula 4 Hydrophilicvarnish 0.05 0.5% tazarotene Formula 5 0.1% tazarotene gel 0.012Results: We Demonstrated:

-   -   that the higher the concentration of active principle, the        greater the penetration of the active principle,    -   that whatever the solvent and the type of film-forming agent,        the active principle at the same dose penetrates in the same        manner,    -   that the addition of urea promotes trans-nail passage in the        case of the polar-type formula.

A second series of tests for penetration was carried out on bovine horn.

These bovine horns were cut so as to obtain disks of keratin having adiameter compatible with that of the Franz cells, these disks having astandardized thickness of 0.6 mm.

The Franz cell used in this experiment is in the form of receptacle withtwo compartments separated by the skin or the horn. In the lowercompartment is a solution of physiological saline thermostated at 37° C.The product to be studied is placed in the upper receptable, in contactwith the skin or the horn. Regular samples are taken from the lowercompartment, in order to study the amounts of active principle.

The varnish containing the tazarotene is deposited onto this disk ofhorn and the trans-nail passage is monitored using C14-labeledtazarotene. The method of studying the penetrating capacity on bovinehorn makes it possible to study the compounds with regard to theirpenetration capacity at a concentration which is effective with respectto the horn, the composition of which is very similar to the compositionof the nail.

7.1 mg/cm² of varnish as defined in formulae 1 to 6 are deposited on thebovine horn.

The contact time was 48 hours, with samples being taken at 6 h, 12 h, 24h, 36 h and 48 h. The nail was cut in sections of 40 microns on adermatome, the surface of the horn and the base of the horn, making up240 microns.

Study of the trans-nail passage of tazarotene over 24 hours Passage inCharacteristic micrograms Formula 1 Hydrophilic varnish 0.001 0.5%tazarotene Formula 2 Hydrophilic varnish 0.05 0.5% tazarotene UreaFormula 3 Lipophilic varnish 2 1% tazarotene Formula 4 Lipophilicvarnish 0.025 0.5% tazarotene

The results were the same. The product with polar solvent and whichcontains urea gives better trans-nail passage.

In conclusion: The nail varnishes containing a film-forming agent and asolvent according to the invention, whether they are based on polarsolvents and on film-forming agents of the same type with or withouturea, or whether they are based on nonpolar solvents, pass through thenail to an extent which makes it possible to attain the therapeuticthreshold.

These varnishes make it possible to obtain rapid and painlesseffectiveness, unlike the other known therapies for this condition.

1. A method for treating psoriasis comprising applying to a nail surfaceor nail polish comprising an effective amount of tazarotene.
 2. A nailvarnish with antipsoriatic action comprising an effective amount oftazarotene.
 3. The nail varnish with antipsoriatic action as claimed inclaim 2, which further comprises a film-forming agent which is solubleor insoluble in polar solvents.
 4. The nail varnish with antipsoriaticaction as claimed in claim 3, which further comprises as a film-formingagent, one or more physiologically acceptable solvents suitable for thetype of film-forming agent used.
 5. The nail varnish with antipsoriaticaction as claimed in claim 4, which comprise one or more penetrationagents and, optionally, additives conventionally used in cosmetics. 6.The nail varnish as claimed in claim 5, characterized in that whereinthe penetration agent is selected from urea, oleic acid andethoxydiglycol.
 7. The nail varnish as claimed in claim 2, whichcomprises tazarotene in an amount ranging from 0.1 to 4% by weightrelative to the total weight of the composition.
 8. The nail varnish asclaimed in claim 7, comprising contains tazarotene in an amount rangingfrom 0.1% to 4% by weight relative to the total weight of thecomposition.
 9. The nail varnish as claimed in claim 3, wherein thefilm-forming agent which is soluble in nonpolar solvents is selectedfrom cellulose nitrate, poly(vinyl acrylate) and partially saponifiedpoly(vinyl acrylate), copolymers of first vinyl acetate and secondlyacrylic acid or crotonic acid or a monoalkyl maleate, ternary copolymersof firstly vinyl acetate and secondly crotonic acid and vinylneodecanoate or crotonic acid and vinyl propionate, copolymers of vinylmethyl ether and of a monoalkyl maleate, copolymers of fatty acid vinylesters and of acrylic acid or of methacrylic acid, copolymers ofN-vinylpyrrolidone, methacrylic acid and alkyl methacrylate, copolymersof acrylic acid and of methacrylic acid, or of alkyl acrylate or ofalkyl methacrylate, poly(vinyl acetals) and poly(vinyl butyrals),poly(N-vinylpyrrolidones) substituted with alkyl groups, alkyl esters ofcopolymers of olefin and of maleic anhydride and products from reactionof rosin and of acrylic acid.
 10. The nail varnish as claimed in claim3, wherein the film-forming agent which is soluble in polar solvents isselected from polyacrylamides; acrylic/methacrylic,polymethacrylate/butyl acrylate and acrylic/acrylate copolymers;polyvinyl alcohol; poly(vinyl methyl ether)/maleic anhydride copolymer;polyvinylpyrrolidone; polyvinylpyrrolidone/vinyl acetate copolymer andvinylpyrrolidone/dimethylaminoethyl methacrylate copolymer.
 11. A methodfor preparing a the nail varnish as claimed in claim 3, comprisingmixing a water-soluble or -insoluble film-forming agent with tazaroteneand, optionally, with other usual components to prepare nail varnishes.12. The nail varnish as claimed in claim 3, further comprising acorticoid or a mixture of various corticoids.
 13. The nail varnish asclaimed in claim 12, wherein the corticoid is selected from clobetasolpropionate or betamethasone dipropionate, betamethasone valerate ordipropionate, flucinolone acetonide and hydrocortisone aceponate orbutyrate, flucinolone acetonide, desonide, and hydrocortisone acetate.14. The nail varnish as claimed in claim 13, wherein the corticoid isclobetasol or one of its pharmaceutically acceptable salts.